CD8 T-cells are important for controlling viral infections and tumors. It remains unclear, however, why CD8 T-cell responses are sometimes unable to clear certain infections or control malignancies. Understanding this failure is important for the rational design of vaccines and therapeutic treatments for persistent viral infections and cancers. We have described effector-function-negative CD8 T-cells during chronic viral infections and have shown that this immunological silencing is more pronounced under conditions of CD4 T-cell deficiency. Since these T-cells arise under conditions of persistent antigenic stimulation it is likely that CD8 T-cells with similar effector-function-negative phenotypes will be found during other chronic viral infections. Such cells are also likely to emerge during persistent antigenic stimulation resulting from tumor outgrowth and this notion is supported by the documentation of unresponsive tumor-associated-antigen specific CD8 T-cells. We hypothesize that exposure of CD8 T cells to persistently high levels of antigen, when CD4 T cell help is limiting, causes the inactivation of the these cells by modulating specific CD8 T cell signal transduction pathways. To specifically address this we propose: 1. To determine the role of antigen load on the induction and maintenance of CD8 T cell unresponsiveness. 2. To determine the contribution of CD4 T cell responses to sustaining CD8 T effector activity. 3. To define the signal transduction pathway that is disrupted in silenced CD8 T cells. Defining the mechanisms which regulate CD8 T cell effector activity during persistent viral infections is of both clinical and fundamental importance. Understanding why CD8 T cell responses become unresponsive under certain conditions has important implications for the development of vaccines and immunotherapeutic approaches to combat infections and malignancies. Furthermore, devising strategies to reactivate preexisting but functionally silenced T cells may facilitate immune mediated clearance of viral infections and tumors.